Neurosteroids that are formed directly within the central nervous system or transported into the brain after being formed in peripheral endocrine tissues modulate neuronal excitability and intraneuronal communication, in large measure, by interacting with cell surface receptors for neurotransmitters such as GABA-A, excitatory amino acids and acetylcholine. Reversible sulfation catalyzed by steroid sulfotransferases and sulfatases have been identified in mammalian brain; however, factors controlling the expression of these activities in discrete brain regions and their specificity for various steroids are not well defined. Accordingly, it is hypothesized that reversible sulfation of neurosteroids by specific sulfotransferases and sulfatases in brain regulates their neuromodulatory activity. This hypothesis will be tested according to the following specific aims: (1) measure the activities of known steroid sulfotransferases/sulfatases in major regions of rat brain and define their distribution in specific groups of cells and neuronal structures using immunohistochemical localization, in.situ. hybridization and reverse transcriptase-PCR; (2) evaluate the capacity of various sulfotransferases and sulfatases expressed in vitro, or inhibited by specific antibodies, to sulfate or hydrolyze steroid sulfates with known neuronal activity; (3) define the gender and developmental profile of various sulfotransferases/sulfatases in rat brain. This research will be initiated during a planned sabbatical beginning in January 1996. Support is sought from March 1996 through August 1996 and for two three-month periods during the summers of 1997 and 1998 to complete studies of the ontogeny of sulfotransferases and sulfatases in male and female rats, and to initiate a study of these activities in human fetal brain.